Cyclopentanophenanthrene derivatives and process



CYCLOPENTANO direct introduction ranatian of thee ductionofrieivvi pregn peutic 'value.

produced in accordance withtlie aforementiii d snea- Uniw AND PROCESS Mexico City, Mexico, assignors to Syntex S.A Moxie;

4 Claims. or. 26045955 introduces a double bond I p ring C and it produces a compound whichiis-g desirable for the direct chemical or biochemical ihtroduction of an HENAN'I'HREM m mvanvrs phenanthrene derivatives and process.

More particularly the present invention deals production of certain novel steroidal sapogenih compounds unsaturated in the 7-8 position.

This application is a division of our applicationSeriai' V a-sans on no oids which possess nqsubstituents in ring C. In addition these derivatives as; useful intermediates since the deg- I In application Seriali/No; 191,941, filed October 24, 1950, now patent No. 286K616, there is disclosed a novel (7-dehydro diosgenin) anti oritlie -esters example the acetate. I Coinpounds pf'this' are tion by selective brominaubrf ofivarious steroidal sapo- .genins possessing the spiro-keial side chain at positions 16 and 17 and also provided with a 3-hydroxy group or the equjvalefitesterithereof as well as a double bond at the S EJBfi'ti n. As; pointed out in this previous application,

sapogeni'fisof this character are' diosgenin and other sapogenins of the ZZ-iso seriesas well as the corresponding 22 normal compolfidsf asi-for example yamogeni-n. Dehydrobrominatipn oi theiicompound selectively bromihas,A -22-isospirostadieneaatedsim b ar see wPiit -l am rid a tay deride-band;atethes aQsit aaia aturat d and-chore;

'- IE5 bass. i enz. further: found iintamiaaeawa No. 191,942, filed Qctober 24 now PatentNo.

In accordance with the present invention it has been flared.- hatults e haa ara em aaeommmd inmat eni'n side chain leads tothe proa'ne derivatives of-potential theraprocess for the production (if AF :22-isospirostadienBfl-ol or the acetateitheriebf :or. otherrsuifableiesten iazdelrydfoe statrien-3p-ol and/ or theiequiyalenti Tdiiscoficompe; a1 2 George Rosenkranz, Jesus Rome, and Carl into flies-1&1 position of the I notion into hitherto inaccessible position. cbr'dince with the present inventibnifil has; also b'en cliseoy ired that dehydrogenation of ;A7+-2-2-isdailo spirostii iifl ol with mercuric acetate in chloroform acetic acid also results in the introduction of a double bond in the 9-11 position to produce the novel A -22-isoallospirostadien-Sfi-ol or the equivalent esters thereof.

Compounds of the character just described have also beenfound to be subjected to degradation insofar as the side chain is concerned so that the treatment of A 22-isoallospirosten-iifi-ol with acetic anhydride at an elevated temperature, as for example 200 C. results in the production of the corresponding A' -allofurostadien-3 8,26-diol (ip-y-diosgenin). The novel compounds may also be further reacted in other ways, for example A' -22-is0a11O spirosten-3B-ol and/or esters thereof may be subjected to rearrangement of the double bond by treatment with a -paladium catalyst in the presence of acetic acid and the double bond rearranges to yield the isomeric A8114 corretural formula: V 1

OH! CH' In the foregoing formula, R is selected from the group consisting of hfili'bgen and an acyl group, i.e, the residue of an alighafidiori aromatic acid, as for example acetic or bengoigacid" residues, although other esters of other organic acids may be th rs represented. In the foregoing formula the group consisting of:

mayehavetotheiisubstituents clfaiaicteiisticiofrtheznaiumlli Itiisetii' be'cundhrstoodithatrincthe above:indicateri'iring 5 structure: the: componndsi'mayabecarlditioiiallyt linsathrate'd iintli'eeQa-fliepositiomoriithewmaiciliaadflitimrallyflinsaxufi ratedain theeSiG anda9== lzlnpositionszauFui thergttlreringt occnrring'sapogenins. The nov be indicated in accordance with the following equation:

hydrogenated talyst In the above equation, R as previously set forth may be hydrogen or the residue of a suitable organic acid such as a fatty acid or an aromatic acid. The first step of the above process may be carried out by selectively hydrogenating the A -22-isospirostadien-3p-ol or a suit able ester thereof such as its acetate with platinum oxide in ethyl acetate solution to yield the desired A' -22-isoallo spirosten-B-fl-ol derivative. In general the reaction can be carried out by dissolving the steroid compound just referred to in a suitable solvent such as ethyl acetate and shaking the same in contact with platinum oxide catalyst in a hydrogen atmosphere until the gas take-up corresponded to exactly one mol, i.e. for a period of time of approximately forty-five minutes. The catalyst can then'be filtered and the filtrate concentrated andcooled to crystallize the product which can then be vrecrystallized el process for the production' of certain of the above exemplified compounds may exemplified by the followingequations:

from a suitable solvent or mixtureof solvents such as chloroform methanol" If the compound thus produced is 76 ally unsaturated in the 9-1 1 position.

as dissolved in a suitable solvent such as ethyl acetate and shaken with palladium-on-charcoal catalyst in an atmosphere of hydrogen in the presence of acetic acid the palladium catalyst aceticacld V cm 7 a c 1- l v CH. O

double bond was rearranged to produce the corresponding A compound. I

A compounds, in accordance with the present invention, which possess additional double bonds as in the 9-11 position of the ring, maybe produced by a' process dehydrogenation s mercurioactata dehydrogenation-1 I mercuric acetate 11 above reactions the appropriate steroid, as for example A -22 isospirostadien-318-01 or 'A' -22isoallospirosten=3 18-01, is dehydrogenated by dissolving the same in a suitable solvent, as for example chloroform, and treated with mercuric acetate and glacial acetic acid by shaking the same at'room temperature for a long period of time,- 1 as for example twenty hours. solution produced-is filtered, more chloroform is added and the acetone is-removed by washing with water and a suitable carbonate. The solution is then dried and evaporated to: produce the equivalent compounds addition- Thereafter' the.

Compounds of the character above described and pro which had crystallized out was redissolved ;by duced in-accordance-wit-hihe preceding equations we be the catalyst was filtered and the filti' atejconce'ntrated partially degraded to :the corrwponding furo'stadieriwonicooled. The colorless crystals were filteredaiidrecrystalpounds as-exemplified by "the-following equation: V lized from chloroform-methanol. m zz-iseahospimsteh- Proceeding in "a c dafl 'fw h i fiv" 5 6 fi h t tfl t n i1 n f 22 i the Steroid c mh nt h xampl 22 '(Q -Q Q Z JQ 'shfifih fi." l IQ l l b l t sten-3,B-ol, is heated with acetic arihydride irr a'bo'nib alcohol with melting point 189.- 9,2 (om,- J 7, tube at 200 C. forapproximately eight hours. The and 'benzoylat ion theben'zoate withihel'tiiig pqint A, acetic anhydride is then hydrolyzed with water and the 223 C.

product extracted with ether, washed with water, dried 25 Example H and evaporated. The oily residue produced was then saponified by refluxing with alcoholic potassium hydrox- One gram of the above acetate of Example I in 150 ide to produce the desired A -allo furostadien-3p,26- cc. of ethyl acetate and 2 cc. of acetic acid was shaken diol. I with 100 mg. of palladium-on-charcoal catalyst in an The 9-11 unsaturated compounds may be treated with atmosphere of hydrogen for twenty-four hours. The a peracid to form the corresponding 9-11 oxides in acreaction could also be carried out in pure acetic acid, cordance with the following equation: but in neither case was any hydrogen absorbed. After 0H3 p on:

OH; CH3 0 I 0 CH3 0 7 0H3 0 I peracld I In accordance with the above equation, as for 'exarnremoval of the catalyst and evaporation of the filtrate ple A' -22-isoallospirostadien-3 3-01 acetate is dis-' to dryness, the residue was recrystallized from ethyl solved in chloroform and mixed with an ethereal soluacetate-methanol. A -22-isoallospirosten-3,B-ol 3-acetion of for example monoperphthalic acid or perbenzoic tate was obtained in nearly quantitative yield with acid. It was then maintained at a low temperature, melting point 197198 C., (a) -72.4 (chloroform). as for example 0 for twenty hours. The reaction mix- Saponification produced the free alcohol, melting point ture is then washed with sodium carbonate solution in 186-189 C., and benzoylation the benzoate with melt- Water, the organic layer evaporated to dryness and the ing point 208-210 C. solid thus produced recrystallized from a suitable sol- I vent such as methanol chloroform. A product was pro- Example In duced believed to be the 9-11-oxido compound, i.e. A solution of 6.0 g. of A 22-isoallospirosten-3fl-ol J P B- 3-acetate- 3-acetate of Example I in 24 cc. of acetic anhydride was In all of the above equations as previously p t heated in a bomb tube at 200 for eight hours. The out, y be y g or y be a suitable y pacetic anhydride was hydrolyzed with water, the product Although in the above equations the iso COmPOUBdS have extracted with ether, washed with Water, dried and evapfi indicated as an p t Same reactions y orated. The oily residue was saponified by refluxing with be Pe d W h the normal 22 p h T is 10 g. of potassium hydroxide and 200 cc. of methanol especially true, 8 1166 On p r l g the Same for one hour. After cooling and diluting with the water,

furostadien is formed from either isomer. the product was extracted with ether, washed to neutral The following Specific examples S61v6 illustmte the with water, dried and concentrated to incipient crystalp invention but are not intended to limit the Same: lization. Filtration and recrystallization from hexaneacetone gave A -allofurostadien-3,3,26-diol' as pale tan pl I crystals with melting point 175-177" C. (Kofier block) A solution of 2.0 g. of A -22-isospirostadien-35-01 3- P Y)- acetate in cc. of ethyl acetate was shaken with 100 Example IV mg. of platinum oxide catalyst for forty-five minutes in a hydrogen atmosphere during which time the gas tip-take A mixture of 12.0 g. of A -22-isoallospirostcn-3B-ol corresponded to exactly one mol. Part of the product 75 B-acetate of Example I, cc. of chloroform, 20 g. of

hours. The yellow solution was filtered, more chloroform was added and then washed thoroughly with water and carbonate to remove all acid, dried and evaporated. Recrystallization of the residue from methanol yielded colorless crystals of A -22-isoallospirostadien-BB- o1 3-acetate with melting point 205-206? C., ((1) -2l, ultra-violet maxima at 234 (10g E 4.17) and 242 mu (log E 4.22).. The free alcohol possessed melting point 177-179 C., (00 35.8, and the benzoate melting point 206-207 C., (00 -24.6.

Example V 272 C., (00 -78.45 and most likely represent A"- 22-isoallo-9,1l-oxidospirosten-bp-ol B-acetate.

8. Example VI The mercuric acetate dehydrogenation of A -22- -isospirostadien 3B-ol 3-acetate was carried out exactly as described for the mono-unsaturated analog in Example IV and lead after recrystallization from methanolethyl acetate to A -22-isospirostatrien-3B-ol 3-acetate with melting point 176-178 C., (00 +1683", ultra-violet maxima at 310 mu (log E 4.18) 324 mu (10g E 4.23) and 338 mu (log E 4.02). The free alcohol had a melting point 187-190? and the benzoate a melting point 197198 C.

We claim:

1. A new compound comprising A' -22-isoallospirosten- 35-01 having a melting point of 189-192 C.

2. An ester of A' -22-isoallospirosten-313-01 selected from the group consisting of lower fatty acid esters and the benzoate esters.

3. A new compound comprising A -22-isoallospirosten- 3fl-ol 3-acetate having a melting point of 222-223 C.

4. A new compound comprising A -22-isoallospirosten- 319-01 3-benzoate having a melting point of 221-223 C.

No references cited. 

2. AN ESTER OF $(-22-ISOALLOSPIROSTEN-3B-OL SELECTED FROM THE GROUP CONSISTING OF LOWER FATTY ACID ESTERS AND THE BENZOATE ESTERS. 